TY - JOUR
T1 - Weight drives caspofungin pharmacokinetic variability in overweight and obese people
T2 - Fractal power signatures beyond two-thirds or three-fourths
AU - Hall, Ronald G.
AU - Swancutt, Mark A.
AU - Meek, Claudia
AU - Leff, Richard
AU - Gumbo, Tawanda
PY - 2013/5
Y1 - 2013/5
N2 - Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergilllosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6)3/4. The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6)3/2, an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing>66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the- concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a "floating" instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at www.clinicaltrials.gov under registration number NCT01062165.)
AB - Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergilllosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6)3/4. The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6)3/2, an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing>66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the- concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a "floating" instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at www.clinicaltrials.gov under registration number NCT01062165.)
UR - http://www.scopus.com/inward/record.url?scp=84876262274&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876262274&partnerID=8YFLogxK
U2 - 10.1128/AAC.01490-12
DO - 10.1128/AAC.01490-12
M3 - Article
C2 - 23459494
AN - SCOPUS:84876262274
SN - 0066-4804
VL - 57
SP - 2259
EP - 2264
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 5
ER -